The neuronal NO synthase participation in the peripheral antinociception mechanism induced by several analgesic drugs

The production of nitric oxide (NO) from l-arginine is catalyzed by NO synthase (NOS), which exists as the following three isoforms: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). The participation of this pathway in peripheral antinociception has been extensively established by our group with the use of several types of drugs, including opioids, cannabinoids, cholinergic, and α2C adrenoceptor agonists and nonsteroidal anti-inflammatory drugs (NSAIDS), and even non-pharmacological procedures such as electroacupuncture. In this study, we aimed to refine the previous data to investigate which type of NOS isoform is involved in the peripheral antinociception mechanism induced by anandamide, morphine, SNC80, bremazocine, acetylcholine, xylazine, baclofen, dipyrone, and diclofenac. After hyperalgesia was induced by intraplantar injection of prostaglandin E2 in male Wistar rats, we measured peripheral nociception with the paw pressure test. All drugs that were used induced a peripheral antinociception effect that was completely blocked by injection of the selective neuronal NO synthase inhibitor, l-NPA (24 μg/paw). The exception was the GABAB agonist baclofen, which induced an effect that was not antagonized. We used the inhibitors l-NIO and -NIL (24 μg/paw) to exclude the involvement of endothelial and inducible NO synthase, respectively. These drugs were ineffective against the antinociception effect induced by all analgesic drugs that we utilized. Based on the experimental evidence, we conclude that the local injection of analgesic drugs activates nNOS to release NO and induce peripheral antinociception.

► Nitric oxide is formed from by three distinct isoenzymes in the NOS family neuronal, endothelial, and inducible.
► It was investigate which of the NOS isoforms is responsible for the peripheral effect induced by an analgesics group.
► Analgesics were antagonized by selective neuronal inhibitor but not by the selective endothelial and inducible inhibitors.
► It was shown that neuronal NOS isoform activation is the first step of the peripheral antinociception of several analgesics.